A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Our most recently analyses have related to assessing the relationships of menopausal hormones to endometrial cancer risk using data from the follow-up study of participants in the Breast Cancer Detections Demonstration Project, a large nation-wide breast screening project. Using approaches similar to previous analyses for breast and ovarian cancer risk, we found strong relationships of risk with unopposed estrogen use, as have been observed by many other investigators. Although risks were less elevated for users of combined estrogen-progestin therapy, they contined to be associated with elevations in risk as compared with non-use. These results therefore raise questions regarding the safety of long-term use of combined replacement therapy. [unreadable] [unreadable] We have also had an interest in effects of other hormonal exposures, including ovulation stimulating drugs used to treat infertility. A retrospective cohort study was also conducted which allowed an assessment of effects on cancer risk of different causes of infertility and associated therapies. This study involved detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. A strength of the study was the detailed information collected on causes of infertility. Analyses showed that type of infertility (primary vs. secondary) was a more important predictor of cancer risk than specific causes of infertility. However, patients with endometriosis were at an especially high risk of developing ovarian cancer. In general, the study provided reassuring results regarding use of ovulation-inducing agents, showing no major increases in cancer risk relating to use of either clomiphene citrate or human menopausal gonadotropins. There were, however, slight increases in risk of both breast and ovarian cancers among the subjects followed for the longest periods of time (15 or 20+ years), supporting the need for additional monitoring of long-term effects of these agents. [unreadable] [unreadable] Certain medical devices have also been of interest, including the long-term safetly of silicone breast implants. Effects on breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. The patients in this study are continuing to be followed for future mortal events, of importance given the aging nature of the study population. We also recently assessed effects on various connective tissue diseases. In general, the results were fairly reassuring, although this investigation did highlight the complexities of evaluating the associations, given the rarity of most individual diseases, and a variety of diagnostic and reporting difficulties. [unreadable] [unreadable] Recent cohort studies demonstrated reduced breast cancer risks among women with a history of fractures or low bone mineral density. The impact of the severity and timing of bone loss on risk has not yet been investigated, and the extent to which other risk factors (family history, anthropometric factors, physical activity, and exogenous hormones) modify the relationship with bone density is unknown. To elaborate on these research questions, we are conducting a follow-up study of over 20,000 postmenopausal women who volunteered for a clinical trial of the bone-enhancing drug alendronate.